History
A 23-year-old woman visits the GP practice nurse because of persistently high blood pres-sure. During the course of her discussion she mentions incidentally that she is cosmeti-cally troubled by ‘lumps’ on her skin, which leads the nurse to refer her to the dermatology clinic. She describes the lumps as asymptomatic but gradually accumulating, particularly over her trunk. She is otherwise well and on no medication. Her parents and sister are also well with no history of hypertension, coronary artery disease or similar skin lesions.
Examination
On examination, her blood pressure is 170/110 mmHg. She has an unusual pigmentary pattern with generalized freckling or lentigines affecting non–sun-exposed sites (such as inframammary, axillae and groin) as well as sun-exposed sites. She has scattered tan-coloured macules over her trunk and proximal legs (12 in total); these macules vary in size, but have a regular shape and borders (Fig. 41.1). She also has soft, fleshy, non-tender, pink to skin-coloured smooth nodules, some of which protrude and are pedunculated and some are located deeper within the dermis. She has normal heart sounds, but she does have a clearly audible right-sided abdominal bruit. The remainder of her examination is normal.
Questions
• What is the diagnosis?
• How should this patient be further investigated?
• What genetic counselling should she receive?
Medicine
The dermatological features (cutaneous neurofibromas with axillary, groin and submam-mary freckling) are pathognomonic of neurofibromatosis type 1 (NF1). Other cutaneous
features of NF1 include hypopigmented macules, cutaneous angiomas, transient xan-thogranulomas and glomus tumours. She has associated hypertension, and the presence of a unilateral bruit is suggestive of renal artery stenosis, a recognized complication of NF1.
Further investigations are not required to confirm a diagnosis of NF1. Molecular test-ing can be considered, and the causative mutation in the NF1 gene can be detected in 95 per cent of cases, but there is not as yet a well-defined genotype–phenotype correla- tion. Imaging studies to look for central nervous system or bony features of NF1 can be performed if symptomatic. There is no medical indication to excise the cutaneous neu-rofibromas as, unlike subcutaneous or plexiform neurofibromas, they are not associated with malignant transformation. They can be a source of psychological distress.
The priority for this patient is to identify the cause of her high blood pressure and initiate appropriate treatment. High blood pressure in NF1 can be a primary process or may be secondary to other NF1 complications, such as renal artery stenosis or phaeo-chromocytoma. This patient should have urgent assessment for renal artery stenosis (including duplex ultrasonography) and 24-hour urinary catecholamine collection to rule out phaeochromocytoma. It is reassuring that her renal function is normal on routine biochemistry, but a protein/creatinine ratio on a random void urine specimen should be performed to assess the level of renal dysfunction and identify any mild to moderate proteinuria which is frequently seen in association with renal vascular disease. NF1 is an autosomal dominant disorder and the responsible gene is located on chromo-some 17. Its protein product, called neurofibromin, is widely expressed particularly in the nervous system. Mutations in the NF1 gene predispose to tumour formation. Formal genetic counselling would be advised before this patient plans pregnancy; she should be informed of a 50 per cent risk of transmitting NF1 to each offspring. The complications of NF1 vary between individuals and are unpredictable within families; there is a 1 in 12 risk for this patient of having a severely affected child. Where a pathogenic NF1 muta-tion is known, both prenatal testing and pre-implantation genetic diagnosis are available. Approximately 50 per cent of affected individuals have new mutations, however the fam-ily of this patient should be examined for any suggestive features.
KEY POINTS
• Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited multisystem condition with major skin features and many potential clinical complications.
• Periodic blood pressure monitoring is part of the routine surveillance of an affected individual.
• Cutaneous features of NF1 include café au lait macules, axillary and groin freckling, neurofibromas, hypomelanotic macules, xanthogranulomas, angiomas and glomus tumours.
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